The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
There is a great need for long-acting drug delivery devices, especially for contraceptives, which require a minimum of medical guidance. This concerns particularly the underdeveloped and developing countries where the medical infrastructure is weak and where family planning can be organized only to an insufficient level.
A great number of subcutaneous implants for female contraception are known in the art. As example can be mentioned the commercially available product Norplant.sup.R, which is an implant having a core containing levonorgestrel as the active substance, and where the core in surrounded by a membrane of a silicone elastomer of poly(dimethylsiloxane) (PDMS). A special preparation of this kind is Jadelle.sup.R in which the core is a poly(dimethylsiloxane) based matrix with levonorgestrel dispersed therein. The membrane is an elastomer made from PDMS and silica filler, which, besides giving necessary strength properties to the membrane, also retards the permeation of the active agent through the membrane.
U.S. Pat. No. 3,854,480 describes a drug delivery device, e.g. an implant, for releasing a drug at a controlled rate for a prolonged period of time. The device has a core of a matrix in which the drug is dispersed. The core is surrounded by a membrane that is insoluble in body fluids. The core matrix as well as the membrane are permeable to the drug by diffusion. The materials of the core and the membrane are chosen so that the drug diffuses through the membrane at a lesser rate than through the core matrix. Thus, the membrane controls the release rate of the drug. As a suitable polymer for the core matrix is mentioned poly(dimethylsiloxane) (PDMS), and as suitable polymers for the membrane are mentioned polyethylene and a copolymer of ethylene and vinyl acetate (EVA).
EP-B1-300306 describes an implant for subcutaneous or local use and for the release of a contraceptive agent for a relatively long time. The contraceptively active substance is dispersed in a core matrix and the core is surrounded by a membrane. As active substances are mentioned highly active progestins such as 3-keto-desogestrel, levonorgestrel and gestodene. The materials of the core matrix and the membrane are both based on copolymers of ethylene and vinyl acetate. The vinyl acetate concentration of the matrix polymer is higher than that of the membrane polymer. Therefore, the drug permeation of the membrane is slower than its permeation of the core matrix.
Androgen based implants for male contraception as well as treatment of benign prostate hypertrophy and other conditions due to hormonal disturbance such as hypogonadism have been described in the art.
U.S. Pat. No. 5,733,565 discloses a male contraceptive implant which comprises 7-.alpha.-methyl-19-nortestosterone (MENT) or 7-.alpha.-methyl-19-Nortestosterone acetate (MENT Ac) as the active agent. The materials of the core matrix and the membrane are both based on copolymers of ethylene and vinyl acetate (EVA). The vinyl acetate concentration of the matrix polymer is higher than that of the membrane polymer. The test results show that an implant releasing MENT AC over a prolonged period of time (about 180 days) is achieved with the EVA copolymer. These results demonstrate an improvement over PDMS based implants containing androgens such as MENT Ac. The latter are useless in practice because of the very rapid release of the androgen.
Devices manufactured from EVA suffer, however, from certain drawbacks. The materials are rather stiff and non-flexible and are therefore rather unconvenient to wear as implants beneath the skin. Moreover, the tests carried out in U.S. Pat. No. 5,733,565 mentioned above, showed that the EVA based system released MENT Ac but did not release MENT in a sufficient amount.
Polysiloxanes, such as PDMS, are preferred polymers in drug delivery devices for a great variety of different drugs. These polymers are particularly useful in subcutaneous implants.
In EP-B1-300306, Example 1, it is mentioned that a polysiloxane layer around the implant did not retard the release rate of the drug. The retarding effect on the drug permeation that can be achieved by mixing silica into the PDMS is, however, rather limited. If silica is mixed into the PDMS polymer to about 40 weight-% of the final elastomer composition, typically a decrease in drug penetration of approximately 20% is achieved. In general, silica loading will have only a minimal influence on the drug permeation The only way to achieve an essentially stronger retardation would be to use a thicker membrane. This would, however, result in devices of greater cross section and this would in turn lead to devices, such as implants and the like, which are difficult to inject and unconvenient to wear.
The cross section of a cylindrical implant should not exceed 3 mm. Preferably, it should be in the range of 1.5 to 2.7 mm. This feature makes demands upon the maximal membrane thickness: the thickness should not be greater than 0.4 mm. The suitable length of the implant should not exceed 50 mm.